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131.
132.
Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease) 总被引:19,自引:0,他引:19
Nishino I Fu J Tanji K Yamada T Shimojo S Koori T Mora M Riggs JE Oh SJ Koga Y Sue CM Yamamoto A Murakami N Shanske S Byrne E Bonilla E Nonaka I DiMauro S Hirano M 《Nature》2000,406(6798):906-910
"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein. 相似文献
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134.
Kidd JM Cooper GM Donahue WF Hayden HS Sampas N Graves T Hansen N Teague B Alkan C Antonacci F Haugen E Zerr T Yamada NA Tsang P Newman TL Tüzün E Cheng Z Ebling HM Tusneem N David R Gillett W Phelps KA Weaver M Saranga D Brand A Tao W Gustafson E McKernan K Chen L Malig M Smith JD Korn JM McCarroll SA Altshuler DA Peiffer DA Dorschner M Stamatoyannopoulos J Schwartz D Nickerson DA Mullikin JC Wilson RK Bruhn L Olson MV Kaul R Smith DR Eichler EE 《Nature》2008,453(7191):56-64
Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale--particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1,695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number between individuals. Complete sequencing of 261 structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence map of human structural variation--a standard for genotyping platforms and a prelude to future individual genome sequencing projects. 相似文献
135.
Kleinman ME Yamada K Takeda A Chandrasekaran V Nozaki M Baffi JZ Albuquerque RJ Yamasaki S Itaya M Pan Y Appukuttan B Gibbs D Yang Z Karikó K Ambati BK Wilgus TA DiPietro LA Sakurai E Zhang K Smith JR Taylor EW Ambati J 《Nature》2008,452(7187):591-597
Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects. 相似文献